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WO2018013559A1 - Nouveaux composés et leurs utilisations - Google Patents

Nouveaux composés et leurs utilisations Download PDF

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Publication number
WO2018013559A1
WO2018013559A1 PCT/US2017/041526 US2017041526W WO2018013559A1 WO 2018013559 A1 WO2018013559 A1 WO 2018013559A1 US 2017041526 W US2017041526 W US 2017041526W WO 2018013559 A1 WO2018013559 A1 WO 2018013559A1
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Prior art keywords
compound according
alkyl
compound
hydroxy
carbon atoms
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PCT/US2017/041526
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English (en)
Inventor
Jie Fan
Ke Liu
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Accutar Biotechnology Inc.
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Priority to KR1020197003884A priority Critical patent/KR20190039125A/ko
Priority to JP2019522609A priority patent/JP2019525955A/ja
Priority to CA3030411A priority patent/CA3030411A1/fr
Priority to EP17828300.8A priority patent/EP3368011A4/fr
Priority to CN201780001677.9A priority patent/CN108495618B/zh
Priority to AU2017297344A priority patent/AU2017297344A1/en
Publication of WO2018013559A1 publication Critical patent/WO2018013559A1/fr
Priority to HK18116445.7A priority patent/HK1257296A1/zh
Priority to HK18116500.9A priority patent/HK1257539A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2503/00—Use of cells in diagnostics
    • C12N2503/02—Drug screening
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • compositions containing such compounds and their use in prevention and treatment of diseases and conditions.
  • Estrogen Receptor alpha is a nuclear receptor that is activated by the hormone estrogen. Upon estrogen binding, Estrogen Receptor alpha undergoes a conformational change and dimerizes, which, along with other regulation factors, leads to a proliferation of cancerous cells. Approximately 75% of breast cancers express Estrogen Receptor alpha and exhibit estrogen- dependent proliferation. Morales, A.R., et al. Am. J. Clin. Path.2005; 123: 21- 27. Estrogen Receptor alpha is implicated in a variety of cancers, such as, but not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer. Breast cancer is the most common cancer among women, and its incidence rate increases every year.
  • SERMs selective estrogen receptor modulators
  • SERMs are compounds that interact with intracellular Estrogen Receptors and act as agonists or antagonists. SERMs are used for treating various estrogen-related diseases, including breast cancer, infertility, ovulatory dysfunction, postmenopausal osteoporosis, estrogen-related gynecomastia, dyspareunia due to menopause, retroperitoneal fibrosis, and idiopathic sclerosing mesenteritis. It has also been reported that SERMs have beneficial effects on serum lipids in postmenopausal women.
  • Tamoxifen is the most commonly used SERM and is widely used in treating Estrogen Receptor alpha positive breast cancer. Unfortunately, Tamoxifen activates other genes, which correlates with an increased incidence of other cancers, for example, endometrial cancer. Bernstein, L. et al. J. Natl Cancer Inst 1999; 91: 1654-62. Further, many cancer patients who receive Tamoxifen will eventually develop resistance. Ring, A. et al. Endocr Relat Cancer 2004; 11: 643-58. Upon failure of Tamoxifen treatment, patients may be prescribed Fulvestrant. Fulvestrant is a selective estrogen receptor degrader via proteasomal degradation.
  • Tamoxifen competes with estrogen to bind to Estrogen Receptor alpha, whereas Fulvestrant is an antagonist. Fulvestrant’s effects are to degrade the Estrogen Receptor alpha protein as opposed to prevent
  • Fulvestrant is an improvement over the deleterious effects of Tamoxifen, Fulvestrant suffers from poor drug-like properties, for example, poor bioavailability and intramuscular administration. Accordingly, there exists a need for an improved method of inhibiting cellular proliferation driven by Estrogen Receptor alpha. Fulvestrant’s mechanism of action, where the proteasome is engaged to degrade Estrogen Receptor alpha, provides an alternative mechanism to inhibiting Estrogen Receptor alpha driven cell proliferation. However, general proteasome degradation is not selective, and therefore could lead to deleterious effects. Accordingly, there is a need to discover and develop a drug that could lead to selective Estrogen Receptor alpha degradation, without the side effects caused by Tamoxifen or Fulvestrant.
  • the present disclosure describes compounds that may be used to bind to both Estrogen Receptor alpha and a ubiquitin ligase.
  • the compounds of the present disclosure possess two binding motifs conjugated via a linker.
  • Estrogen Receptor alpha degradation may occur when both Estrogen Receptor alpha and a ubiquitin ligase are bound and brought into close proximity.
  • X 1 is selected from CH 2 , NR 8 , O, and S;
  • R 1 is selected from H, C 1 -C 6 alkyl, halo, heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 2 is selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 4 is selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • each R 5 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy;
  • R 6 , R 7 , and R 8 are each independently selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 9 is selected from H, C 1 -C 6 alkyl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • L* is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(O), O, NR 4 , S, C 2 -alkenyl, C 2 - alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • R 1 is selected from H, C 1 -C 6 alkyl, halo, heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 2 is selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, halo, and hydroxy, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 4 is selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • each R 5 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy;
  • R 6 and R 7 is each independently selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • L is a linker of 6 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • R 1 is selected from H, C 1 -C 6 alkyl, halo, heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 2 is selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, halo, and hydroxy, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 4 is selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ; each R 5 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy;
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • L 1 is a linker of 9 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. [11] In some embodiments,
  • R 1 is selected from H, C 1 -C 6 alkyl, halo, heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 2 is selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, halo, and hydroxy, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 4 is selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ; each R 5 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy;
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • L 2 is a linker of 6 to 7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. [13] In some embodiments, L 2 may be
  • L may contain at least one O atom. In some embodiments, L may contain at least one aryl. In some embodiments, L may contain at least one C 2 -alkenyl. In some embodiments, L may contain at least one C 2 -alkynyl. In some embodiments, L may contain at least one 5- membered heteroaryl. In some embodiments, the at least one 5-membered heteroaryl may be a triazole.
  • L 1 may contain at least one O atom. In some embodiments, L 1 may contain at least one aryl. In some embodiments, L 1 may contain at least one C 2 -alkenyl. In some embodiments, L 1 may contain at least one C 2 -alkynyl. In some embodiments, L 1 may contain at least one 5- membered heteroaryl. In some embodiments, the at least one 5-membered heteroaryl may be a triazole.
  • L 2 may contain at least one O atom. In some embodiments, L 2 may contain at least one aryl. In some embodiments, L 2 may contain at least one C 2 -alkenyl. In some embodiments, L 2 may contain at least one C 2 -alkynyl. In some embodiments, L 2 may contain at least one 5- membered heteroaryl. In some embodiments, the at least one 5-membered heteroaryl may be a triazole.
  • R 1 may be selected from halo and heteroaryl. In some embodiments, R 1 may be a 5-membered heteroaryl. In some embodiments, R 1 may be methylthiazole. In some embodiments, R 1 may be 4-methylthiazole. In some embodiments, R 1 may be .
  • R 2 may be C 1 -C 6 alkyl. In some embodiments, R 2 may be tert-butyl. In some embodiments, R 2 may be iso- propyl.
  • R 3 may be H. In some embodiments, R 3 may be C 1 -C 6 alkyl. In some embodiments, R 3 may be hydroxy.
  • R 4 may be H. In some embodiments, R 4 may be C 1 -C 3 alkyl. In some embodiments, C 1 -C 3 may be methyl. In some embodiments, R 4 may be acyl. In some embodiments, the acyl may be acetyl.
  • R 6 may be C 1 -C 3 alkyl. In some embodiments, the C 1 -C 3 alkyl may be methyl. In some embodiments, the R 6 may be H.
  • R 7 may be selected from H and C 1 -C 3 alkyl. In some embodiments, R 7 may be H. In some embodiments, R 7 may be C 1 -C 3 alkyl. In some embodiments, the C 1 -C 3 alkyl may be methyl. [23] In some embodiments, provided herein is the compound:
  • a pharmaceutical composition comprising the compound of Formulae (I), (II), (III), or (IV), and at least one additional component selected from pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, and pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising the compound of Formulae (I), (II), (III), or (IV), and at least one additional component selected from pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, and pharmaceutically acceptable excipients.
  • composition wherein the compound may be present in a therapeutically effective amount.
  • provided herein is a method of treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of the compound of Formulae (I), (II), (III), or (IV), or of the pharmaceutical composition provided herein, wherein the cancer may be chosen from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or esophageal cancer.
  • the cancer may be breast cancer.
  • the cancer may be positive for Estrogen Receptor alpha.
  • the subject may have been previously treated with an anti-cancer agent.
  • the anti- cancer agent may be tamoxifen.
  • provided herein is a use of the compound of Formulae (I), (II), (III), or (IV) in a method of therapeutic treatment, wherein said therapeutic treatment may be treatment of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, esophageal cancer, infertility, ovulatory dysfunction, postmenopausal osteoporosis, estrogen-related gynecomastia, dyspareunia due to menopause, retroperitoneal fibrosis, or idiopathic sclerosing mesenteritis.
  • provided herein is a use of the compound of Formulae (I), (II), (III), or (IV) in the preparation of a medicament.
  • provided herein is a method of inhibiting cell growth, comprising contacting a cell with the compound of Formulae (I), (II), or (III), or a pharmaceutical composition provided herein.
  • the cell may be a cancer cell. In some embodiments, the cell may express Estrogen Receptor alpha.
  • Figure 1A illustrates Compound 1 bound to Estrogen Receptor alpha and a Von Hippel-Lindau ligase
  • Figure 1B is an alternative view of the protein-ligand complex illustrated in Figure 1A;
  • Figure 2 illustrates the degradative activity of a compound of the present disclosure toward Estrogen Receptor alpha
  • Figure 3A illustrates the comparative degradative activity of several compounds of the present disclosure toward Estrogen Receptor alpha
  • Figure 3B illustrates the comparative degradative activity of several compounds of the present disclosure toward Estrogen Receptor alpha
  • Figures 4A, 4B, and 4C show Estrogen Receptor alpha activity as a function of varying linker length
  • Figure 5 illustrates a comparison of Estrogen Receptor alpha activity when cells are treated with compounds of high structural similarity
  • Figure 6 illustrates the Estrogen Receptor alpha activity of cells after treatment with various compounds
  • Figure 7 illustrates the time course of Estrogen Receptor alpha degradation induced by a compound of the present disclosure
  • Figure 8 illustrates the time course of Estrogen Receptor alpha degradation induced by various compounds
  • Figure 9A illustrates the proteasome-dependence of Estrogen Receptor alpha degradation
  • Figure 9B illustrates the proteasome-dependence of Estrogen Receptor alpha degradation
  • Figure 10A illustrates the anti-proliferation activity of a compound of the present disclosure toward the Estrogen Receptor alpha positive cell line MCF-7;
  • Figure 10B illustrates the lack of anti-proliferation activity toward the triple negative (i.e., Estrogen Receptor alpha negative breast cancer MB- 231 cell line;
  • Figure 11 illustrates the degradative activity of a compound of the present disclosure in another Estrogen Receptor alpha positive cell line T-47D;
  • Figure 12 illustrates the plasma concentration of Compound 1 as a function of time after administration of various formulations
  • Figure 13 illustrates the Estrogen Receptor alpha degradation in a tumor
  • Figures 14A, 14B, and 14C show the effect of treatment on tumor weight and volume
  • Figure 15A illustrates the effect on cell proliferation after administration of either Compound 1 or tamoxifen.
  • Figure 15B illustrates the effect on Estrogen Receptor alpha degradation after administration of either Compound 1 or tamoxifen.
  • cancer refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body.
  • exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.
  • Subject refers to an animal, such as a mammal, that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful for both human therapy and veterinary applications. In one embodiment, the subject is a human.
  • treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof.
  • treatment refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient.
  • treatment or “treating” refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
  • treatment or “treating” refers to delaying the onset of a disease or disorder. For example, treating a cholesterol disorder may comprise decreasing blood cholesterol levels.
  • prevention or “preventing” refers to a reduction of the risk of acquiring a given disease or disorder.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CN is attached through the carbon atom.
  • acyl refers to R-C(O)- groups such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality.
  • acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl.
  • a C 4 -acyl has three other ring or chain atoms plus carbonyl.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C 2- C 8 )alkenyl.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as (C 1 -C 8 )alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2- propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1- propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl- 1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
  • “alkyl” is a straight-chain hydrocarbon.
  • “alkyl” isopropyl
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C 2 - C 8 )alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4- propyl-2-pentynyl, and 4-butyl-2-hexynyl.
  • aryl refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system with 5 to 14 ring atoms.
  • the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, heteroaryls, and heterocyclyls.
  • aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • Exemplary aryl groups also include, but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as“C 6 -aryl.”
  • cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as“(C 3 -C 8 )cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
  • Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc.
  • the term“cycloalkyl” also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.
  • the terms“halo” or“halogen” as used herein refer to -F, -Cl, -Br, and/or -I.
  • heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • Heteroaryls can also be fused to non-aromatic rings.
  • Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
  • heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C 2 -C 5 )heteroaryl.”
  • heterocycle refers to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur.
  • Heterocycles can be aromatic (heteroaryls) or non-aromatic.
  • Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycly
  • Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
  • Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl,
  • pharmaceutically acceptable carrier refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • prodrugs as used herein represents those prodrugs of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure.
  • a discussion is provided in Higuchi et al., “Prodrugs as Novel Delivery Systems,” ACS Symposium Series, Vol.14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American
  • compositions refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i
  • salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or
  • stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated“( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.
  • the compound is a racemic mixture of (S)- and (R)-isomers.
  • provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration.
  • the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more.
  • the compound mixture has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
  • the compound mixture has an (R)- enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more.
  • the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more.
  • Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • Geometric isomers can also exist in the compounds of the present disclosure.
  • the present disclosure encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
  • Substituents around a carbon-carbon double bond are designated as being in the“Z” or“E” configuration wherein the terms“Z” and“E” are used in accordance with IUPAC standards.
  • structures depicting double bonds encompass both the E and Z isomers.
  • carbocyclic ring are designated as“cis” or“trans.”
  • the term“cis” represents substituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated“cis/trans.”
  • structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium ( 2 H) or tritium ( 3 H), or the replacement of a carbon by a 13 C- or 14 C-carbon atom are within the scope of this disclosure.
  • Such compounds may be useful as, for example, analytical tools, probes in biological assays, or therapeutic agents.
  • X 1 is selected from CH 2 , NR 8 , O, and S;
  • R 1 is selected from H, C 1 -C 6 alkyl, halo, heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 2 is selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 4 is selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • each R 5 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy;
  • R 6 , R 7 , and R 8 are each independently selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 9 is selected from H, C 1 -C 6 alkyl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • L* is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(O), C(NH), C(S), O, NR 4 , S, C 2 - alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • R 1 is selected from H, C 1 -C 6 alkyl, halo, heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 2 is selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, halo, and hydroxy, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 4 is selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • each R 5 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy;
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • L is a linker of 6 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • R 1 is selected from H, C 1 -C 6 alkyl, halo, heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 2 is selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, halo, and hydroxy, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 4 is selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • each R 5 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy;
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • L 1 is a linker of 9 to 10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • R 1 is selected from H, C 1 -C 6 alkyl, halo, heterocycle, and heteroaryl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 2 is selected from H, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl, halo, and hydroxy, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • R 4 is selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • each R 5 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy;
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 ;
  • L 2 is a linker of 6 to 7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may range from 1 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(O), C(NH), C(S), O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L* may range from about 6 carbon atoms to about 16 carbon atoms, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may range from about 6 carbon atoms to about 11 carbon atoms, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L* may range from about 6 carbon atoms to about 9 carbon atoms, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may be 6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 - alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L* may be 7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may be 8 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L* may be 9 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may be 10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L* may be 11 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 - alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may be 12 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L* may be 13 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may be 14 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 - alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L* may be 15 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may be 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L* may be 1 carbon atom in length. In some embodiments, L* may be 2 carbon atoms in length. In some
  • L* may be 3 carbon atoms in length. In some embodiments, L* may be 4 carbon atoms in length. In some embodiments, L* may be 5 carbon atoms in length. In some embodiments, L* may be 6 carbon atoms in length. In some embodiments, L* may be 7 carbon atoms in length. In some
  • L* may be 8 carbon atoms in length. In some embodiments, L* may be 9 carbon atoms in length. In some embodiments, L* may be 10 carbon atoms in length. In some embodiments, L* may be 11 carbon atoms in length. In some embodiments, L* may be 12 carbon atoms in length. In some embodiments, L* may be 13 carbon atoms in length. In some embodiments, L* may be 14 carbon atoms in length. In some embodiments, L* may be 15 carbon atoms in length. In some embodiments, L* may be 16 carbon atoms in length.
  • L* may be 6 carbon atoms in length, wherein 2 carbon atoms have been replaced by O. In some embodiments, L* may be 8 carbon atoms in length, wherein 2 carbon atoms have been replaced by O. In some embodiments, L* may be 9 carbon atoms in length, wherein 3 carbon atoms have been replaced by O. In some embodiments, L* may be 11 carbon atoms in length, wherein 3 carbon atoms have been replaced by O. In some embodiments, L* may be 14 carbon atoms in length, wherein 4 carbon atoms have been replaced by O. In some embodiments, L* may be 15 carbon atoms in length, wherein 5 carbon atoms have been replaced by O.
  • L* may be 1 carbon atom in length, wherein the one carbon atom is optionally replaced by a cycloalkyl. In some embodiments, L* may be 1 carbon atom in length, wherein the one carbon atom is optionally replaced by a heterocycle. In some embodiments, L* may be 1 carbon atom in length, wherein the one carbon atom is optionally replaced by an aryl. In some embodiments, L* may be 1 carbon atom in length, wherein the one carbon atom is optionally replaced by a heteroaryl. In some embodiments, L* may be 1 carbon atom in length, wherein the one carbon atom is optionally replaced by a C 2 -alkenyl. In some embodiments, L* may be 1 carbon atom in length, wherein the one carbon atom is optionally replaced by a C 2 -alkynyl.
  • L* may be 2 carbon atoms in length, wherein one carbon atom is optionally replaced by a cycloalkyl. In some embodiments, L* may be 2 carbon atoms in length, wherein one carbon atom is optionally replaced by a heterocycle. In some embodiments, L* may be 2 carbon atoms in length, wherein one carbon atom is optionally replaced by an aryl. In some embodiments, L* may be 2 carbon atoms in length, wherein one carbon atom is optionally replaced by a heteroaryl.
  • L* may be 3 carbons in length, wherein one carbon atom is optionally replaced by a C 2 -alkenyl. In some embodiments, L* may be 4 carbon atoms in length, wherein one carbon atom is optionally replaced by a C 2 -alkenyl. In some embodiments, L* may be 5 carbon atoms in length, wherein one carbon atom is optionally replaced by a C 2 -alkenyl. In some embodiments, L* may be 6 carbon atoms in length, wherein one carbon atom is optionally replaced by a C 2 -alkenyl.
  • L* may be 3 carbons in length, wherein one carbon atom is optionally replaced by a C 2 - alkynyl. In some embodiments, L* may be 4 carbon atoms in length, wherein one carbon atom is optionally replaced by a C 2 -alkynyl. In some embodiments, L* may be 5 carbon atoms in length, wherein one carbon atom is optionally replaced by a C 2 -alkynyl. In some embodiments, L* may be 6 carbon atoms in length, wherein one carbon atom is optionally replaced by a C 2 -alkynyl.
  • L* may be 4 carbon atoms in length, wherein two carbon atoms are each optionally replaced by a C 2 -alkenyl. In some embodiments, L* may be 5 carbon atoms in length, wherein two carbon atoms are each optionally replaced by a C 2 -alkenyl. In some embodiments, L* may be 6 carbon atoms in length, wherein two carbon atoms are each optionally replaced by a C 2 -alkenyl. In some embodiments, L* may be 4 carbon atoms in length, wherein two carbon atoms are each optionally replaced by a C 2 -alkynyl.
  • L* may be 5 carbon atoms in length, wherein two carbon atoms are each optionally replaced by a C 2 -alkynyl. In some embodiments, L* may be 6 carbon atoms in length, wherein two carbon atoms are each optionally replaced by a C 2 -alkynyl.
  • L* may be 4 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O). In some embodiments, L* may be 5 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O). In some embodiments, L* may be 6 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O).
  • L* may be 7 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O). In some embodiments, L* may be 8 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O). In some embodiments, L* may be 9 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O).
  • L* may be 10 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O). In some embodiments, L* may be 11 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O). In some embodiments, L* may be 12 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O).
  • L* may be 13 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O). In some embodiments, L* may be 14 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O). In some embodiments, L* may be 15 carbon atoms in length, wherein a first carbon atom is optionally replaced by O or NR 4 and a second carbon atom is optionally replaced by C(O).
  • L* may be selected from L, L 1 , and L 2 . In some embodiments, L* may be L. In some embodiments, L* may be L 1 . In some embodiments, L* may be L 2 . [93] In some embodiments, L* may be In some embodiments, L* may be . In some embodiments, L* may be n some embodiments, L* may be In some embodiments, L* may be
  • L* may be . In some embodiments, L* may be
  • L* may be
  • L* may be
  • L* may be . In some embodiments, L* may be . In some embodiments, L* may be In some embodiments, L* may be In some embodiments, L* may be . In some embodiments, L* may be In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L*, L* may be . In some embodiments, L*, L* may be . In some embodiments, L*, L* may be . In some embodiments, L*, L* may be . In some embodiments, L*, L*
  • L* may be .
  • L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some
  • L* may be . In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be In some embodiments, L* may be . In some embodiments, L* may be . In some embodiments, L* may be
  • X 1 may be selected from CH 2 , NR 8 , O, and S. In some embodiments, X 1 may be CH 2 . In some embodiments, X 1 may be NR 8 . In some embodiments, X 1 may be O. In some embodiments, X 1 may be S.
  • R 8 may be selected from H, C 1 -C 6 alkyl, and acyl, each of which may be substituted with 0, 1, 2, or 3 R 5 .
  • R 8 may be selected from H, C 1 -C 6 alkyl, and acyl.
  • R 8 may be H.
  • R 8 may be C 1 -C 6 alkyl, substituted with 0, 1, 2, or 3 R 5 .
  • R 8 may be C 1 -C 6 alkyl.
  • R 8 may be C 1 alkyl.
  • R 8 may be C 1 alkyl, substituted with 0, 1, 2, or 3 R 5 .
  • R 8 may be acyl.
  • R 8 may be acyl, substituted with 0, 1, 2, or 3 R 5 .
  • R 9 may be selected from H, C 1 -C 6 alkyl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 5 .
  • R 9 may be H.
  • R 9 may be halo.
  • R 9 may be halo, where the halo is fluoro.
  • R 9 may be halo, where the halo is chloro.
  • R 9 may be hydroxy.
  • R 9 may be sulfhydryl.
  • R 9 may be C 1 -C 6 alkyl. In some embodiments, R 9 may be C 1 alkyl. In some embodiments, R 9 may be C 1 alkyl, substituted with 0, 1, 2, or 3 R 5 . In some embodiments, R 9 may be C 1 alkyl.
  • L may range from about 6 carbon atoms to about 16 carbon atoms, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L may range from about 6 carbon atoms to about 16 carbon atoms, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L may range from about 6 carbon atoms to about 11 carbon atoms, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L may range from about 6 carbon atoms to about 9 carbon atoms, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L may be 6 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 - alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L may be 7 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L may be 8 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L may be 9 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L may be 10 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L may be 11 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L may be 12 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L may be 13 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 - alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L may be 14 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. In some embodiments, L may be 15 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.
  • L may be 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by O, NR 4 , S, C 2 - alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl. [101] In some embodiments, L may be 6 carbon atoms in length. In some embodiments, L may be 7 carbon atoms in length. In some
  • L may be 8 carbon atoms in length. In some embodiments, L may be 9 carbon atoms in length. In some embodiments, L may be 10 carbon atoms in length. In some embodiments, L may be 11 carbon atoms in length. In some embodiments, L may be 12 carbon atoms in length. In some embodiments, L may be 13 carbon atoms in length. In some embodiments, L may be 14 carbon atoms in length. In some embodiments, L may be 15 carbon atoms in length. In some embodiments, L may be 16 carbon atoms in length.
  • L may be 6 carbon atoms in length, wherein 2 carbon atoms have been replaced by O. In some embodiments, L may be 8 carbon atoms in length, wherein 2 carbon atoms have been replaced by O. In some embodiments, L may be 9 carbon atoms in length, wherein 3 carbon atoms have been replaced by O. In some embodiments, L may be 11 carbon atoms in length, wherein 3 carbon atoms have been replaced by O. In some embodiments, L may be 14 carbon atoms in length, wherein 4 carbon atoms have been replaced by O. In some embodiments, L may be 15 carbon atoms in length, wherein 5 carbon atoms have been replaced by O.
  • R 1 may be C 1 -C 6 alkyl. In some embodiments, R 1 may be methyl. In some embodiments, R 1 may be ethyl. In some embodiments, R 1 may be iso-propyl. In some embodiments, R 1 may be tert-butyl.
  • R 1 may be heterocycle. In some embodiments, R 1 may be heteroaryl. In some embodiments, R 1 may be a 5- membered heteroaryl. In some embodiments, R 1 may be thiazole. In some embodiments, R 1 may be oxazole. In some embodiments, R 1 may be a 5- membered heteroaryl substituted with 1 R 5 . In some embodiments, R 1 may be a 5-membered heteroaryl substituted with 1 R 5 , wherein the R 5 is methyl. In some embodiments, R 1 may be thiazole substituted with 1 R 5 . In some embodiments, R 1 may be thiazole substituted with 1 R 5 , wherein the R 5 is methyl. In some embodiments, R 1 may be . In some embodiments, R 1 may be pyrimidine.
  • R 1 may be halo. In some embodiments, R 1 may be fluoro. In some embodiments, R 1 may be chloro. In some embodiments, R 1 may be bromo. In some embodiments, R 1 may be iodo. In some embodiments, R 1 may be H.
  • R 2 may be H. In some embodiments, R 2 may be C 1 -C 6 alkyl. In some embodiments, R 2 may be C 1 -C 3 alkyl. In some embodiments, R 2 may be C 2 -C 4 alkyl. In some embodiments, R 2 may be methyl. In some embodiments, R 2 may be ethyl. In some embodiments, R 2 may be iso-propyl. In some embodiments, R 2 may be tert-butyl.
  • R 2 may be C 3 -C 6 cycloalkyl. In some embodiments, R 2 may be cyclopropyl. In some embodiments, R 2 may be cyclobutyl. In some embodiments, R 2 may be cyclopentyl. In some
  • R 2 may be cyclohexyl.
  • R 3 may be H. In some embodiments, R 3 may be hydroxy. In some embodiments, R 3 may be C 1 -C 6 alkyl. In some embodiments, R 3 may be C 1 -C 4 alkyl. In some embodiments, R 3 may be methyl. In some embodiments, R 3 may be ethyl. In some embodiments, R 3 may be iso-propyl. In some embodiments, R 3 may be tert-butyl.
  • R 3 may be halo. In some embodiments, R 3 may be fluoro. In some embodiments, R 3 may be chloro. In some embodiments, R 3 may be chloro. In some embodiments, R 3 may be bromo. In some embodiments, R 3 may be iodo.
  • R 4 may be H. In some embodiments, R 4 may be C 1 -C 6 alkyl. In some embodiments, R 4 may be C 1 -C 3 alkyl. In some embodiments, R 4 may be methyl. In some embodiments, R 4 may be acyl. In some embodiments, R 4 may be acetyl.
  • R 5 may be C 1 -C 6 alkyl. In some embodiments, R 5 may be C 1 -C 4 alkyl. In some embodiments, R 5 may be methyl. In some embodiments, R 5 may be ethyl. In some embodiments, R 5 may be iso-propyl. In some embodiments, R 5 may be tert-butyl.
  • R 5 may be halo. In some embodiments, R 5 may be fluoro. In some embodiments, R 5 may be chloro. In some embodiments, R 5 may be bromo. In some embodiments, R 5 may be iodo.
  • R 6 may be selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 .
  • R 6 may be H. In some membodiments, R 6 may be C 1 -C 6 alkyl. In some embodiments, R 6 may be C 1 -C 3 alkyl. In some embodiments, R 6 may be methyl. In some embodiments, R 6 may be acyl. In come embodiments, R 6 may be C 1 -C 3 acyl. In come embodiments, R 6 may be acetyl.
  • R 7 may be selected from H, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 5 .
  • R 7 may be H.
  • R 7 may be C 1 -C 6 alkyl.
  • R 7 may be C 1 -C 3 alkyl.
  • R 7 may be C 1 -C 3 alkyl.
  • R 7 may be methyl.
  • R 7 may be C 1 -C 3 acyl.
  • R 7 may be acetyl.
  • L may be In some embodiments, L may be . In some embodiments, L may be . In some embodiments, L may be
  • L 1 may be
  • L 1 may be In some embodiments, L 1 may be In some embodiments, L 1 may be In some embodiments, L 1 may be In some embodiments, L 1 may be In some embodiments, L 1 may be In some embodiments, L 1 may be
  • L 2 may be . In some embodiments, L 2 . In
  • L 2 may be . In some embodiments, L 2
  • the compound 4-(5- (((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5- oxopentyl)benzyl (2-(4-((Z)-1,2-diphen
  • the compound 6-(2- (((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2- oxoethoxy)hex-4-yn-1-yl (2-
  • N1- (3-((2-(4-((Z)-1,2-bis(4-hydroxyphenyl)but-1-en-1- yl)phenoxy)ethyl)(methyl)amino)-3-oxopropyl)-N4-((S)-1-((2S,4R)-4-hydroxy-2- ((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1- oxobutan-2-yl)succinamide.
  • compositions of the present disclosure comprise at least one compound of Formulae (I), (II), (III), or (IV), or tautomer,
  • stereoisomer, pharmaceutically acceptable salt or hydrate thereof formulated together with one or more pharmaceutically acceptable carriers include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration.
  • parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
  • the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients).
  • the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
  • the carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • a unit-dose formulation for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • Other pharmacologically active substances may also be present including other compounds.
  • the formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.
  • liquid compositions conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one compound of Formulae (I), (II), or (III), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof, which are approximately isotonic with the blood of the intended recipient.
  • These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection.
  • Such preparations may conveniently be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood.
  • Injectable compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of the active compound.
  • Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the active compound i.e., at least one compound of Formulae (I), (II), (III), or (IV), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof
  • the active compound i.e., at least one compound of Formulae (I), (II), (III), or (IV), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof
  • the amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.
  • a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 ⁇ g to about 1000 mg.
  • intermittent administration such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed.
  • Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect.
  • physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.
  • a therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used.
  • the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma
  • Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Compositions that exhibit large therapeutic indices are preferable.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered to treat cancer in a subject in need thereof.
  • the cancer is chosen from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.
  • the cancer is breast cancer.
  • the cancer is lung cancer.
  • the cancer is ovarian cancer.
  • the cancer is endometrial cancer.
  • the cancer is prostate cancer.
  • the cancer is esophageal cancer.
  • the cancer is positive for Estrogen Receptor alpha.
  • a compound of Formulae (I), (II), or (III), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered as a pharmaceutical composition.
  • the subject has been previously treated with tamoxifen.
  • the therapeutic treatment is for the treatment of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.
  • the therapeutic treatment is for the treatment of breast cancer.
  • the therapeutic treatment is for lung cancer.
  • the therapeutic treatment is for the treatment of ovarian cancer.
  • the therapeutic treatment is for the treatment of endometrial cancer.
  • the therapeutic treatment is for the treatment of prostate cancer.
  • the therapeutic treatment is for the treatment of esophageal cancer. In some embodiments, the therapeutic treatment is for the treatment of estrogen-related diseases and conditions. In some embodiments, the therapeutic treatment is for the treatment of infertility. In some embodiments, the therapeutic treatment is for the treatment of ovulatory dysfunction. In some embodiments, the therapeutic treatment is for the treatment of postmenopausal osteoporosis. In some embodiments, the therapeutic treatment is for the treatment of estrogen-related gynecomastia. In some embodiments, the therapeutic treatment is for the treatment of dyspareunia due to menopause. In some embodiments, the therapeutic treatment is for the treatment of
  • the therapeutic treatment is for the treatment of idiopathic sclerosing mesenteritis.
  • a method of inhibiting cell growth comprising contacting a cell with a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof.
  • the cell may express Estrogen Receptor alpha.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered in combination with another therapeutic agent.
  • the other therapeutic agent can provide additive or synergistic value relative to the administration of a compound of the present disclosure alone.
  • the therapeutic agent can be selected from, for example, hormones and hormonal analogues; signal transduction pathway inhibitors; topoisomerase I inhibitors;
  • the therapeutic agent may be a hormone or hormonal analogue.
  • the therapeutic agent may be a signal transduction pathway inhibitor.
  • the therapeutic agent may be a topoisomerase I inhibitor.
  • the therapeutic agent may be a hormone or hormonal analogue.
  • the therapeutic agent may be a signal transduction pathway inhibitor.
  • the therapeutic agent may be a topoisomerase I inhibitor.
  • therapeutic agent may be a topoisomerase II inhibitor.
  • the therapeutic agent may be an antimetabolite neoplastic agent.
  • the therapeutic agent may be an antibiotic neoplastic agent.
  • the therapeutic agent may be an alkylating agent.
  • the therapeutic agent may be an anti-microtubule agent.
  • the therapeutic agent may be a platinum coordination complex.
  • the therapeutic agent may be an aromatase inhibitor.
  • the therapeutic agent may be an anti-mitotic agent.
  • the aromatase inhibitor may be selected from anastrazole, letrozole, vorozole, fadrozole, exemestane, and formestane.
  • the aromatase inhibitor is anastrazole.
  • the aromatase inhibitor may be letrozole.
  • the aromatase inhibitor may be vorozole.
  • the aromatase inhibitor may be fadrozole.
  • the aromatase inhibitor may be exemestane.
  • the aromatase inhibitor may be formestane.
  • the anti-mitotic agent may be selected from paclitaxel, docetaxel, and Abraxane.
  • the anti- mitotic agent may be paclitaxel.
  • the anti-mitotic agent may be docetaxel.
  • the anti-mitotic agent may be Abraxane.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with a hormone or hormonal analog.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with a signal transduction pathway inhibitor.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with an antimetabolite neoplastic agent.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with a topoisomerase I inhibitor.
  • a compound of Formulae (I), (II), (III), (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with a topoisomerase II inhibitor.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with an aromatase inhibitor.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with one or more anti-cancer agents.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with an anti-cancer agent, wherein the anti-cancer agent is tamoxifen.
  • a compound of Formulae (I), (II), (III), or (IV), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof may be administered in combination with an anti-cancer agent, wherein the anti-cancer agent is fulvestrant.
  • the chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques well known in the art. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from about -10° C to about 200° C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10° C to about 200° C over a period that can be, for example, about 1 to about 24 hours; reactions left to run overnight in some embodiments can average a period of about 16 hours.
  • protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the (R)- and (S)-isomers of the nonlimiting exemplary compounds can be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes which can be separated, e.g., by crystallization; via formation of diastereoisomeric derivatives which can be separated, e.g., by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, e.g., enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, e.g., on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a chiral environment e.g., on a chiral support, such as silica with a bound chiral ligand
  • a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.
  • disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, e.g., from Aldrich Chemical
  • DMEM Dulbecco’s Modification of Eagle’s Medium 4.
  • DMSO dimethylsulfoxide
  • FBS fetal bovine serum
  • MCF-7 Michigan Cancer Foundation-7 breast cancer cell line 17.
  • NMR nuclear magnetic resonance
  • PVDF polyvinylidene fluoride
  • SDS sodium dodecyl sulfate
  • Example 1 was purified by reverse- phase preparative HPLC to afford Example 1 as a white solid (220 mg, 57%).
  • Example 2 (71 mg, 48%) as a white solid.
  • N 1 -(2-(4-((Z)-1,2-Diphenylbut-1-en-1-yl)phenoxy)ethyl)-N 4 -((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 1 - methylsuccinamide Obtained as a white solid (20 mg, 82%).
  • N 1 -(2-(4-((Z)-1,2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N 6 -((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 1 - methyladipamide Obtained as a white solid (20 mg, 80%).
  • MCF-7 cells were maintained in high glucose DMEM (Corning cellgro, 15-013-CM), supplemented with 10% FBS, 1X L-Glutamine (29.2 mg/mL) and 1X Penicillin Streptomycin (10,000 I.U./mL Penicillin; 10,000 ⁇ g/mL Streptomycin; Corning, 30-009-CI).
  • the resulting MCF-7 cells were plated into a 24-well plate at 1 ⁇ 10 5 cells/well, and the following day, compound was added to the cell medium at various concentrations. After treating the cell medium with compound, the cell plates were incubated for 20 hours at 37° C. Upon cooling, cells were lysed by addition of SDS loading buffer.
  • the resulting cell lysates were subjected to immunoblotting by standard protocol. with primary antibodies of mouse anti-human ER ⁇ monoclonal antibody (Santa Cruz Biotechnology Inc., #SC-8002) and 1:1000 goat anti-human actin polyclonal antibody (Santa Cruz Biotechnology Inc. #SC-1616). Western blot results visualized using
  • the membranes were then incubated with Primary antibodies mouse anti-ER ⁇ (1:500, Santa Cruz Biotechnology), or goat anti- actin (1:4,000, Santa Cruz Biotechnology) overnight at 4° C, followed by washing 3 times with TBST, and then incubated with horseradish peroxidase– conjugated rabbit anti-mouse or anti-goat IgG (1:5,000) for 1 hour. After TBST washes, blots were developed with an enhanced chemiluminescence kit (Thermo Fisher Scientific). The bands were imaged by chemidock touch system (Bio-Rad) and quantified by ImageJ.
  • FIG.4A shows Estrogen Receptor alpha degradation as a function of linker length for compounds of the formula: .
  • FIG.4B shows Estrogen Receptor alpha degradation as a function of linker length for compounds of the formula:
  • FIG.4C shows the relationship between Estrogen Receptor alpha degradation IC 50 and linker length.
  • Table 3 contains the IC 50 values depicted in FIG.4C:
  • Estrogen Receptor alpha was studied. It was surprisingly found that the presence of the carbonyl adjacent to the tamoxifen moiety is critical, as shown in FIG.5. Compound B was found to be ten-fold more potent than Compound A, lacking the critical carbonyl group. Example 6. Comparison of Estrogen Receptor alpha degradation activity of compounds of the present disclosure and various literature compounds.
  • MCF-7 cells were treated with compounds A, B, and C, as described in Example 5. As shown in FIG.5, compound A, of the present disclosure, is more potent than both compounds B and C.
  • MCF-7 cells were maintained in high glucose DMEM (Corning cellgro, 15-013-CM), supplemented with 10% FBS, 1x L-Glutamine (29.2 mg/mL), and Penicillin Streptomycin (10,000 I.U./mL Penicillin; 10,000 ⁇ g/mL Streptomycin; Corning, 30-009-CI). These cells were then plated into 24-well plate at 1 ⁇ 10 5 cells/well, and Compound 1 was added to each well of the 24- well plate at a final concentration of 100 nM the following day. The cells were lysed at 1, 2, 4, 8, 24, and 48 hours.
  • FIG.7 depicts the degradative activity of Compound 1 at various time points over the course of 48 hours.
  • Estrogen Receptor alpha as a function of time, is shown in FIG.8, for compounds A-D.
  • MCF-7 cells were maintained in high glucose DMEM (Corning cellgro, 15-013-CM) supplemented with 10% FBS, 1x L-Glutamine (29.2 mg/mL), and Penicilin Streptomycin (10,000 I.U./mL Penicillin; 10,000 ⁇ g/mL Streptomycin; Corning, 30-009-CI). These cells were plated into 24-well plates at 1 ⁇ 10 5 cells/well, and the following day Compound 1 (
  • FIG.9A illustrates the proteasome dependence of Estrogen Receptor alpha degradation induced by compounds of the present disclosure.
  • FIG.9B shows the effect of treatment using Compound 1 alone and in the presence of tamoxifen and expomicin, at 100 nM, 10 ⁇ M, and 1 ⁇ M respectively.
  • Example 9 Compounds of the present disclosure demonstrate selectivity for cells with Estrogen Receptor alpha.
  • MCF-7 cells were maintained in high glucose DMEM (Corning cellgro, 15-013-CM) supplemented with 10% FBS, 1x L-Glutamine (29.2 mg/mL), and Penicilin Streptomycin (10,000 I.U./mL Penicillin; 10,000 ⁇ g/mL Streptomycin; Corning, 30-009-CI). These cells were plated into 24-well plates at 2 ⁇ 10 4 cells/well, and the following day Compound 1 (
  • FIGS.10A and 10B demonstrate the compounds of the present disclosure for cells that are selective for Estrogen Receptor alpha positive (10A) over Estrogen Receptor alpha negative (10B).
  • Example 10 Compounds of the present disclosure are active against other cell types that are positive for Estrogen Receptor alpha.
  • T47D cells were maintained in RPMI 1640 , supplemented with 10% FBS, 1x L-Glutamine (29.2 mg/mL), and Penicillin Streptomycin (10,000 I.U./mL Penicillin; 10,000 ⁇ g/mL Streptomycin; Corning, 30-009-CI) and 5 ⁇ g/mL Bovine insulin.
  • the resulting T47D cells were plated into a 24-well plate at 1 ⁇ 10 5 cells/well, and the following day, compound was added to the cell medium at various concentrations. After treating the cell medium with compound, the cell plates were incubated for 20 hours. Upon cooling, cells were lysed. The resulting cell lysates were subjected to immunoblotting by standard protocol with primary antibodies of mouse anti-human ER ⁇
  • FIG.11 shows the effect induce by Compound 1 on Estrogen Receptor alpha degradation at various concentrations.
  • Example 11 Pharmacokinetic study of a compound of the present disclosure.
  • mice Nine mice were divided into three groups, with three mice per group. Each mouse was orally administered one of the formulations described above, at 50 mg/kg. The dosing volume administered was 10 mL/kg. Group 1 was administered Formulation 1, and the mice in group 1 were in a fed state. Group 2 was administered Formulation 2, and the mice in group 2 were in a fasted state. Group 3 was administered Formulation 3, and the mice in group 3 were in a fed state.
  • FIG.12 shows that administration of Formulations 1 and 2 resulted in appreciable amounts of Compound 1 in the blood at the 4 hour time point.
  • Table 7 shows the pharmacokinetic parameters for the various formulations.
  • Example 12 Measurement of Estrogen Receptor alpha expression in MCF-7 breast cancer xenograft model.
  • mice Female BALB/c nude mice (with supplemental 17- ⁇ estradiol) bearing MCF-7 tumors (mean tumor volume 200 mm 3 ) were treated with Compound 1 (5 mg/kg, 3 doses/day, i.p.) in vehicle or by vehicle only for 1 day.
  • vehicle solution is: 10% Ethanol, 20% Solutol, 20% PG, 50% Captisol.
  • tumor tissues from each animal were collected and subjected to western blot analysis for ER ⁇ and Actin.
  • Example 13 Compounds of the present disclosure inhibit cancer cell growth in a MCF-7 breast cancer-derived mouse xenograft model.
  • mice Female BALB/c nude mice (supplemented with 17- ⁇ estradiol) bearing MCF-7 tumors (mean tumor volume was 211 mm 3 ) were treated with
  • tumor volume [length ⁇ width 2 ]/2)
  • FIG.14A shows a significant decrease in tumor weight for the mice in the treatment group versus the mice in the control group.
  • FIGS.14B and 14C show tumor volume and tumor volume percent change, respectively, as a function of time for the mice in the treatment group versus mice in the control group.
  • Example 14 Assessment of compound activity in tamoxifen-resistant tumor cells
  • Compound 1 was compared with that of tamoxifen and fulvestrant. LTED cells were plated into 96-well plates at 0.3 ⁇ 10 4 cells/well and assayed for 4 days. Compounds were added to medium at different final concentrations as indicated in the results. Media were replaced each day during compound exposure.
  • FIG.15A shows change in cell number as a function of inhibitor concentration.
  • FIG.15B shows change in Estrogen Receptor alpha expression as a function of inhibitor concentration.

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Abstract

La présente invention concerne de nouveaux composés, des compositions pharmaceutiques contenant de tels composés, et leur utilisation dans la prévention et le traitement de maladies et d'états associés aux oestrogènes.
PCT/US2017/041526 2016-07-12 2017-07-11 Nouveaux composés et leurs utilisations WO2018013559A1 (fr)

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CA3030411A CA3030411A1 (fr) 2016-07-12 2017-07-11 Nouveaux composes et leurs utilisations
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WO2020142227A1 (fr) * 2019-01-03 2020-07-09 The Regents Of The University Of Michigan Agents de dégradation de protéine récepteur des oestrogènes
US11642342B2 (en) * 2019-12-23 2023-05-09 Accutar Biotechnology Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer

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US20220016102A1 (en) * 2018-11-21 2022-01-20 Shanghaitech University Er protein regulators and use thereof
WO2020106933A1 (fr) 2018-11-21 2020-05-28 Accutar Biotechnology Inc. Nouveaux composés ayant une activité de dégradation des récepteur des oestrogènes alpha et leurs utilisations
CN112390852B (zh) * 2019-08-14 2022-10-18 上海济煜医药科技有限公司 作为蛋白降解剂的化合物及其制备方法和应用
WO2021118629A1 (fr) * 2019-12-12 2021-06-17 Accutar Biotechnology Inc. Nouveaux dérivés de chromane ayant une activité de dégradation des récepteurs des oestrogènes et leurs utilisations

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US11642342B2 (en) * 2019-12-23 2023-05-09 Accutar Biotechnology Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer

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US20200024269A1 (en) 2020-01-23
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